SOD1 Mutants -- Possible Culprit?
Because we know for certain that the mutations of the SOD1 gene are responsible for a subset of ALS cases, most scientists and clinicians believe there’s great value in understanding how mutated SOD1 causes cells to die. Even though most ALS patients lack these mutations, scientists believe clarifying what the mutations do will shed light on more typical forms of the disease. Investigators refer to the resulting lines of research as theories on SOD1 mediated neural toxicity.

These theories include the possibility:

1. that mutated SOD1 codes for an abnormal protein that, in turn, causes oxidative damage (removes electrons from a molecule and alters it for the worse). This idea is the basis for the anti-oxidant therapies that some patients currently take—anti-oxidant vitamins and medications meant to reverse this effect. Ongoing research on both patients and mice carrying the SOD1 mutation has found signs of oxidative tissue damage.

   Yet much controversy has brewed over proving that this oxidative process is what truly causes the nerve cell insults of ALS. Although oxidative damage does in fact occur in the disease, some researchers believe it’s a secondary, downstream effect that doesn’t significantly reflect what goes awry due to the mutations. Pioneering work by many of the Center’s investigators has looked into oxidative injury as a possible key mechanism for SOD1 toxicity. Because of these studies, they now downplay its importance.

2. Copper mediated toxicity—another of the SOD1 injury theories— has suggested that mutant SOD1's resulting protein may be toxic because it mishandles the metal ion copper. Normal SOD1—which is an enzyme— requires copper for its activity. Without copper, SOD1 cannot act as a normal anti-oxidant enzyme. Because of new studies at the Center, however, researchers have begun to suggest that toxicity due to copper "mishandling" may not be the principal cause of nerve cell death.

3. Protein aggregation. A third theory hinges on the idea that abnormal SOD1 proteins begin to accumulate or aggregate and the sheer mass of protein is somehow toxic to cells, either directly or because of some important secondary process it hinders. Center scientists have indeed found large accumulations of excess protein in the motor neurons that die in ALS, as well as in astrocytes —the supportive cells that lie adjacent to motor neurons. Abnormal protein begins to collect well in advance of actual clinical disease.

   Protein aggregation is a particularly "hot" area of scientific investigation, not only for ALS but also in research on Alzheimer’s, Huntington’s and Parkinson’s disease. Center scientists have begun unusually wide-reaching research to understand the role of toxic aggregates in nerve cell injury and death. They’re also observing effects in astrocytes, to see if selective injury of these cells may trigger or somehow influence damage of motor neurons.

Still, for the majority of ALS cases, we do not know what causes the disease. Researchers haven’t been idle, however, and several attractive theories exist on what could cause or contribute to the death of motor neurons in ALS. Center scientists are focusing on these pathogenic theories.